SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity.

Boysen, Gunther; Rodrigues, Daniel N; Rescigno, Pasquale; Seed, George; Dolling, David; Riisnaes, Ruth; Crespo, Mateus; Zafeiriou, Zafeiris; Sumanasuriya, Semini; Bianchini, Diletta; Hunt, Joanne; Moloney, Deirdre; Perez-Lopez, Raquel; Tunariu, Nina; Miranda, Susana; Figueiredo, Inês; Ferreira, Ana; Christova, Rossitza; Gil, Veronica; Aziz, Sara; ... (2018). SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity. Clinical cancer research, 24(22), pp. 5585-5593. American Association for Cancer Research 10.1158/1078-0432.CCR-18-0937

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deletions and mutations frequently cooccur in prostate cancer with lower frequencies reported in castration-resistant prostate cancer (CRPC). We monitored CHD1 expression during disease progression and assessed the molecular and clinical characteristics of -deleted/-mutated metastatic CRPC (mCRPC). We identified 89 patients with mCRPC who had hormone-naive and castration-resistant tumor samples available: These were analyzed for CHD1, PTEN, and ERG expression by IHC. status was determined by targeted next-generation sequencing (NGS). We studied the correlations between these biomarkers and (i) overall survival from diagnosis; (ii) overall survival from CRPC; (iii) duration of abiraterone treatment; and (iv) response to abiraterone. Relationship with outcome was analyzed using Cox regression and log-rank analyses. CHD1 protein loss was detected in 11 (15%) and 13 (17%) of hormone-sensitive prostate cancer (HSPC) and CRPC biopsies, respectively. Comparison of CHD1 expression was feasible in 56 matched, same patient HSPC and CRPC biopsies. CHD1 protein status in HSPC and CRPC correlated in 55 of 56 cases (98%). We identified 22 patients with somatic mutations, with six of these mutations not reported previously in prostate cancer. mutations and/or CHD1 loss was associated with a higher response rate to abiraterone (SPOP: OR, 14.50 = 0.001; CHD1: OR, 7.30, = 0.08) and a longer time on abiraterone (SPOP: HR, 0.37, = 0.002, CHD1: HR, 0.50, = 0.06).-mutated mCRPCs are strongly enriched for CHD1 loss. These tumors appear highly sensitive to abiraterone treatment. .

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